Nonsteroidal progesterone receptor modulators

ABSTRACT

This invention relates to nonsteroidal progesterone receptor modulators of general formula I,  
                 
a process for their production, the use of progesterone receptor modulators for the production of pharmaceutical agents as well as pharmaceutical compositions that contain these compounds. The compounds according to the invention are suitable for therapy and prophylaxis of gynecological diseases, such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhea, as well as for the therapy and prophylaxis of hormone-dependent tumors and for use for female birth control as well as for hormone replacement therapy.

This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 60/693,404 filed Jun. 24, 2005.

This invention relates to nonsteroidal progesterone receptor modulators, a process for their production, the use of progesterone receptor modulators for the production of pharmaceutical agents as well as pharmaceutical compositions that contain these compounds.

The steroid hormone progesterone regulates the reproductive process in the female organism in a decisive way. During the cycle and in pregnancy, progesterone is secreted in large amounts from the ovary or the placenta. By interaction with estrogens, progesterone produces cyclic changes of the uterine mucous membrane (endometrium) in the menstrual cycle. Under the influence of elevated progesterone levels after ovulation, the uterine mucous membrane is converted into a state that allows the nidation of an embryo (blastocyte). In pregnancy, progesterone controls the relaxation of the myometrium and retains the function of the decidual tissue.

In addition, it is known that progesterone inhibits the endometrial proliferation by the suppression of the estrogen-mediated mitosis in the uterus tissue (K. Chwalisz, R. M. Brenner, U. Fuhrmann, H. Hess-Stumpp, W. Elger, Steroids 65, 2000, 741-751).

An important role of the progesterone and the progesterone receptors is also known in pathophysiological processes. Progesterone receptors are detected in foci of endometriosis, but also in tumors of the uterus, the breast and the CNS. In addition, it is known that uterus leiomyomas grow in a progesterone-dependent manner.

The actions of progesterone in the tissues of genital organs and in other tissues are carried out by interactions with progesterone receptors, which are responsible for the cellular effects.

Progesterone receptor modulators are either pure agonists or partially or completely inhibit the action of progesterone. Consequently, substances are defined as pure agonists, partial agonists (SPRMS) and pure antagonists.

According to the ability of the progesterone receptor modulators to influence the action of the progesterone receptor, these compounds have a considerable potential as therapeutic agents for gynecological and oncological indications as well as for obstetrics and birth control.

Pure progesterone receptor antagonists completely inhibit the action of progesterone in the progesterone receptor. They have antiovulatory properties as well as the ability to inhibit estrogen effects in the endometrium up to full atrophy. They are therefore especially suitable for intervening in the female reproductive process, e.g., in post-ovulation, to prevent nidation; in pregnancy, to increase the reactivity of the uterus to prostaglandins or oxytocin or to ensure the opening and softening (“maturation”) of the cervix as well as to make the myometrium highly prepared for labor.

In foci of endometriosis or in tumor tissue, which are (is) equipped with progesterone receptors, an advantageous influence of the disease process is expected after application of pure progesterone receptor antagonists. Special advantages for influencing pathologic conditions, such as endometriosis or uterus leiomyomas, could then be given if in addition an inhibition of the ovulation can be achieved by the progesterone receptor antagonists. When ovulation is inhibited, a portion of the ovarian hormone production and thus the stimulative effect that is due to this portion are also due to the pathologically altered tissue.

A large number of analogs with varying degrees of progesterone receptor-antagonistic activity followed the first described progesterone receptor antagonist RU 486 (also mifepristone). While RU 486, in addition to the progesterone receptor-antagonistic action, also shows an antiglucocorticoidal action, compounds synthesized later are distinguished primarily by a more selective action than progesterone receptor antagonists.

From the literature, in addition to steroidal compounds such as onapristone or lilopristone, which are distinguished from progesterone-receptor-antagonistic action to antiglucorticoidal action relative to RU 486 by a better dissociation of action, various nonsteroidal structures, whose antagonistic action on the progesterone receptor is examined, are also known [see, e.g., S. A. Leonhardt and D. P. Edwards, Exp. Biol. Med. 227: 969-980 (2002) and R. Winneker, A. Fensome, J. E. Wrobel, Z. Zhang, P. Zhang, Seminars in Reproductive Medicine, Volume 23: 46-57 (2005)]. Previously known compounds, however, have only moderately antagonistic activity compared to the known steroidal structures. The most effective nonsteroidal compounds are described as having in vitro activities of 10% of the activity of RU 486.

The antiglucocorticoidal activity is disadvantageous for a therapeutic application in which the inhibition of the progesterone receptors is a primary focus of therapy. An antiglucocorticoidal activity causes undesirable side effects in the case of therapeutically necessary dosages. This can prevent the application of a therapeutically useful dose or lead to termination of the treatment.

The partial or complete reduction of the antiglucocorticoidal properties is therefore an important requirement for the therapy with progesterone receptor antagonists, in particular for those indications that require a treatment lasting weeks or months.

In contrast to the pure antagonists, progesterone receptor partial agonists (SPRMs) show a residual agonistic property, which can be strongly pronounced to different degrees. This leads to the fact that these substances show potential agonistic actions of the progesterone receptor in specific organ systems (D. DeManno, W. Elger, R. Garg, R. Lee, B. Schneider, H. Hess-Stumpp, G. Schuber, K. Chwalisz, Steroids 68, 2003, 1019-1032). Such an organ-specific and dissociated action can be of therapeutic use for the indications described.

It is therefore the object of this invention to make available additional nonsteroidal progesterone receptor modulators. These compounds are to have a reduced antiglucocorticoidal action and are therefore suitable for the therapy and prophylaxis of gynecological diseases such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhea. In addition, the compounds according to the invention are to be suitable for the therapy and prophylaxis of hormone-dependent tumors, for example breast, endometrial, ovarian and prostate cancers. In addition, the compounds are to be suitable for use in female birth control and for female hormone replacement therapy.

The object is achieved according to this invention by the preparation of non-steroidal compounds of general formula I

in which

-   -   R¹ and R², independently of one another, mean a hydrogen atom, a         straight or nonstraight, branched or unbranched C₁-C₅-alkyl         group, also together with the C atom of the chain forming a ring         with a total of 3-7 members,     -   R³ means a radical C≡C—R^(a), whereby         -   R^(a) means a hydrogen or a C₁-C₈-alkyl, C₂-C₈-alkenyl,             C₂-C₈-alkinyl, C₃-C₁₀-cycloalkyl, or heterocycloalkyl that             optionally is substituted in one or more places, in the same             way or differently, with K, or an aryl or heteroaryl that             optionally is substituted in one or more places, in the same             way or differently, with L,             -   K is a cyano, halogen, hydroxy, nitro, —C(O)R^(b),                 CO₂R^(b), —O—R^(b), —S—R^(b), SO₂NR^(c)R^(d),                 —C(O)—NR^(c)R^(d), —OC(O)—NR^(c)R^(d), or                 —C═NOR^(b)—NR^(c)R^(d) or a C₃-C₁₀-cycloalkyl that                 optionally is substituted in one or more places, in the                 same way or differently, with M, heterocycloalkyl, or                 aryl or heteroaryl that optionally is substituted in one                 or more places with L,             -   L means C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkinyl,                 C₁-C₆-perfluoroalkyl, C₁-C₆-perfluoroalkoxy,                 C₁-C₆-alkoxy-C₁-C₆-alkoxy, (CH₂)_(p)—C₃-C₁₀-cycloalkyl,                 (CH₂)_(p)-heterocycloalkyl, (CH₂)_(p)CN, (CH₂)_(p)Hal,                 (CH₂)_(p)NO₂, (CH₂)_(p)—C₆-C₁₂-aryl,                 (CH₂)_(p)-heteroaryl, —(CH₂)_(p)PO₃(R^(b))₂,                 -   —(CH₂)_(p)NR^(c)R^(d), —(CH₂)_(p)NR^(e)COR^(b),                     —(CH₂)_(p)NR^(e)CSR^(b), —(CH₂)_(p)NR^(e)S(O)R^(b),                     —(CH₂)_(p)NR^(e)S(O)₂R^(b),                     —(CH₂)_(p)NR^(e)CONR^(c)R^(d),                     —(CH₂)_(p)NR^(e)COOR^(b),                     —(CH₂)_(p)NR^(e)C(NH)NR^(c)R^(d),                     —(CH₂)_(p)NR^(e)CSNR^(c)R^(d),                     —(CH₂)_(p)NR^(e)S(O)NR^(c)R^(d),                     —(CH₂)_(p)NR^(e)S(O)₂NR^(c)R^(d), —(CH₂)_(p)COR^(b),                     —(CH₂)_(p)CSR^(b), —(CH₂)_(p)S(O)R^(b),                     —(CH₂)_(p)S(O)(NH)R^(b), —(CH₂)_(p)S(O)₂R^(b),                     —(CH₂)_(p)S(O)₂NR^(c)R^(d), —(CH₂)_(p)SO₂OR^(b),                     —(CH₂)_(p)CO₂R^(b), —(CH₂)_(p)CONR^(c)R^(d),                     —(CH₂)_(p)CSNR^(c)R^(d), —(CH₂)_(p)OR^(b),                     —(CH₂)_(p)SR^(b), —(CH₂)_(p)CR^(b)(OH)—R^(e),                     —(CH₂)_(p)—C═NOR^(b), —O—(CH₂)_(n)—O—,                     —O—(CH₂)_(n)—CH₂—, —O—CH═CH— or —(CH₂)_(n+2)—,                     whereby n=1 or 2, and the terminal oxygen atoms                     and/or carbon atoms are linked to directly adjacent                     ring-carbon atoms,             -   M means C₁-C₆-alkyl or a group —COR^(b), CO₂R^(b),                 —O—R^(b), or —NR^(c)R^(d), whereby                 -   R^(b) means a hydrogen or a C₁-C₆-alkyl,                     C₂-C₈-alkenyl, C₂-C₈-alkinyl, C₃-C₁₀-cycloalkyl,                     C₆-C₁₂-aryl or C₁-C₃-perfluoroalkyl, and                 -   R^(c) and R^(d), independently of one another, mean                     a hydrogen, C₁-C₆-alkyl, C₂-C₈-alkenyl,                     C₂-C₈-alkinyl, C₃-C₁₀-cycloalkyl, C₆-C₁₂-aryl,                     C(O)R^(b) or a hydroxy group, whereby if                 -   R^(c) is a hydroxy group, R^(d) can be only one                     hydrogen, a C₁-C₆-alkyl, C₂-C₈-alkenyl,                     C₂-C₈-alkinyl, C₃-C₁₀-cycloalkyl or C₆-C₁₂-aryl and                     vice versa, and                 -   R^(e) means a hydrogen, C₁-C₆-alkyl, C₂-C₈-alkenyl,                     C₂-C₈-alkinyl, C₃-C₁₀-cycloalkyl or C₆-C₁₂-aryl, and                 -   p can be a number from 0-6, or     -   R³ is a radical C═C—R^(g)R^(h), whereby         -   R^(g) and R^(h), independently of one another, are a             hydrogen or a C₁-C₈-alkyl, C₂-C₈-alkenyl or C₂-C₈-alkinyl             that optionally is substituted in one or more places, in the             same way or differently, with X, in which             -   X is a cyano, halogen, hydroxy, nitro, —C(O)R^(b),                 CO₂R^(b), —O—R^(b), —C(O)—NR^(c)R^(d), —NR^(c)R^(d) with                 the meanings already further mentioned above for R^(b),                 R^(c) and R^(d), and     -   R^(4a) and R^(4b), independently of one another, mean a hydrogen         atom, a C₁-C₄-alkyl, a C₂-C₄-alkenyl or together with the         ring-carbon atom forming a 3- to 6-membered ring,     -   A means a monocyclic or bicyclic, carbocyclic or heterocyclic         aromatic ring, which optionally can be substituted in one or         more places with C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkinyl,         C₁-C₆-perfluoroalkyl, C₁-C₆-perfluoroalkoxy,         C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy,         (CH₂)_(p)—C₃-C₁₀-cycloalkyl, (CH₂)_(p)-heterocycloalkyl,         (CH₂)_(p)CN, (CH₂)_(p)Hal, (CH₂)_(p)NO₂, (CH₂)_(p)—C₆-C₁₂-aryl,         (CH₂)_(p)-heteroaryl, —(CH₂)_(p)PO₃(R^(b))₂,         —(CH₂)_(p)NR^(c)R^(d), —(CH₂)_(p)NR^(e)COR^(b),         —(CH₂)_(p)NR^(e)CSR^(b), —(CH₂)_(p)NR_(e)S(O)R^(b),         —(CH₂)NR^(e)S(O)₂R^(b), —(CH₂)_(p)NR^(e)CONR^(c)R^(d),         —(CH₂)_(p)NR^(e)COOR^(b), —(CH₂)_(p)NR^(e)C(NH)NR^(c)R^(d),         —(CH₂)_(p)NR^(e)CSNR^(c)R^(d), —(CH₂)_(p)NR^(e)S(O)NR^(c)R^(d),         —(CH₂)_(p)NR^(e)S(O)₂NR^(c)R^(d), —(CH₂)_(p)COR^(b),         —(CH₂)_(p)CSR^(b), —(CH₂)_(p) S(O)R^(b),         —(CH₂)_(p)S(O)(NH)R^(b), (CH₂)_(p)S(O)₂R^(b),         —(CH₂)_(p)S(O)₂NR^(c)R^(d), —(CH₂)_(p)SO₂OR^(b),         —(CH₂)_(p)CO₂R^(b), —(CH₂)_(p)CONR^(c)R^(d),         —(CH₂)_(p)CSNR^(c)R^(d), —(CH₂)_(p)OR^(b), —(CH₂)_(p)SR^(b),         —(CH₂)_(p)CR^(b)(OH)—R^(d), —(CH₂)_(p)—C═NOR^(b),         —O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, —O—CH═CH— or —(CH₂)_(n+2)—,         whereby n=1 or 2, and the terminal oxygen atoms and/or carbon         atoms are linked to directly adjacent ring-carbon atoms, or     -   A means a radical —CO₂R^(b), C(O)NR^(c)R^(d), COR^(b), or     -   A means an alkenyl group —CR⁵═CR⁶R⁷, whereby         -   R⁵, R⁶ and R⁷ are the same or different and, independently             of one another, mean hydrogen atoms, halogen atoms, aryl             radicals or an unsubstituted or partially or completely             fluorinated C₁-C₅-alkyl group, or     -   A means an alkinyl group —C≡CR⁵, with the meaning cited above         for R⁵ and     -   B means a carbonyl group or a CH₂ group as well as their         pharmaceutically acceptable salts.

The compounds of general formula I according to the invention can be present as different stereoisomers because of the presence of asymmetry centers. Both the racemates and the separately present stereoisomers are part of the subject of this invention.

In addition, this invention comprises the new compounds as pharmaceutical active ingredients, their production, their therapeutic application and pharmaceutical dispensing forms that contain the new substances.

The compounds of general formula (I) according to the invention or their pharmaceutically acceptable salts can be used for the production of a pharmaceutical agent, especially for treatment and prophylaxis of gynecological diseases, such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhea. In addition, the compounds according to the invention can be used for the treatment and prophylaxis of hormone-dependent tumors, such as, for example, for breast, prostate and endometrial cancers.

The compounds of general formula (I) according to the invention or their pharmaceutically acceptable salts are suitable for use for female birth control or for female hormone replacement therapy.

A process for the production of the compounds of general formula (I), moreover, is also a subject of this invention. Substituent R³ is introduced to a keto group by selective addition reaction of organometallic compounds such as lithium alkinylene or magnesium haloalkinylene. This results, either directly or after implementing additional modifications, in the compounds of general formula (I) according to the invention.

The production of the compounds according to the invention is carried out by selective addition of organometallic compounds to ketoamides, which were described in, e.g., laid-open specifications WO 200375915 and WO 9854159. The organometallic compounds can be, for example, lithium alkinyl compounds or magnesium haloalkinyl compounds. The latter are produced by, e.g., reaction of the corresponding alkines with butyllithium or Grignard compounds. Analogously to this, the corresponding organometallic alkenyl compounds can also be produced. The reactivity of the keto group in comparison to amidocarbonyl or to phthalide is in this case significantly higher, such that with suitable selection of the reaction conditions, a selective addition is achieved. As an alternative, the alkinyl or alkenyl radicals that are introduced as R³ can also be further modified later. For these modifications, reactions that have become known to one skilled in the art, such as oxidation, reduction, substitution, alkylation, or palladium-catalyzed reaction, are suitable. Optionally present protective groups are cleaved off at a suitable time.

The nonsteroidal compounds of general formula I according to the invention have a strongly antagonistic or strongly partially agonistic action on the progesterone receptor. They exhibit a strong dissociation of action with respect to their bonding strength on the progesterone receptor and on the glucocorticoid receptor. While known progesterone receptor antagonists, such as Mifepristone (RU 486), in addition to the desired high binding affinity for the progesterone receptor likewise show a high affinity for the glucocorticoid receptor, the compounds according to the invention are distinguished by a very low glutocorticoid receptor bond with simultaneously present high progesterone receptor affinity.

The substituents of the compounds of general formula I according to the invention that are defined as groups can have the meanings below in each case:

C₁-C₅—, C₁-C₆— or C₁-C₈-alkyl groups are defined as straight or nonstraight, branched or unbranched alkyl radicals. In this case, for example, this is a methyl, ethyl, n-propyl, iso-propyl, n-, iso-, tert-butyl, an n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl, hexyl, heptyl or octyl group.

In terms of R^(a), in this case, the methyl, ethyl, n-propyl or n-butyl group as well as an n-pentyl group are preferred.

In terms of R¹ and R², methyl or ethyl is preferred.

According to the invention, a hydrogen is preferred for R4^(a) and R4^(b).

Alkenyl is defined as straight or nonstraight, branched or unbranched alkenyl radicals. In terms of the invention, a C₂-C₈-alkenyl group is defined, for example, as follows: vinyl, allyl, 3-buten-1-yl- or 2,3-dimethyl-2-propenyl. If aromatic compound A is substituted with a C₂-C₈-alkenyl radical, this is preferably a vinyl group.

Alkinyl is defined as straight or nonstraight, branched or unbranched alkinyl radicals. For example, an ethinyl, propinyl, butinyl, pentinyl, hexinyl or octinyl group, but preferably an ethinyl or propinyl group, is to stand for a C₂-C₈-alkinyl radical.

For C₃-C₁₀-cycloalkyl, for example, cyclopropane, cyclobutane, cyclopentane and cyclohexane can be mentioned. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.

In terms of R^(a), K or L, heterocycloalkyl is defined as 3- to 8-membered heterocycloalkyl radicals. Examples of heterocycloalkyl are morpholine, tetrahydrofuran, pyran, piperazine, piperidine, pyrrolidine, oxirane, oxetane, aziridine, dioxolane and dioxane. In this case, the position of the heteroatom in relation to the point of linkage can be any chemically possible position.

For example, methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy can stand for a C₁-C₆-alkoxyl-C₁-C₆-alkoxy group.

b

In terms of the invention, a radical OR^(b) is a hydroxy, methoxy, ethoxy, n-propoxy, iso-propoxy, n-, iso-, or tert-butoxy group, or an n-pentoxy, 2,2-dimethylpropoxy or 3-methylbutoxy group. Hydroxy, methoxy and ethoxy are preferred.

For a partially or completely fluorinated C₁-C₅-alkyl group, the perfluorinated alkyl groups that appear above are considered. Of the latter, primarily the trifluoromethyl group or the pentafluoroethyl group as well as as partially fluorinated alkyl groups, for example the 5,5,4,4-pentafluoropentyl group or the 5,5,5,4,4,3,3-heptafluoropentyl group, are preferred.

-   -   A fluorine, chlorine, bromine or iodine atom can stand for a         halogen atom. Preferred here is fluorine, chlorine or bromine.     -   If R¹ and R² together with the C atom of the chain form a 3- to         7-membered ring, this is, for example, a cyclopropyl,         cyclobutyl, cyclopentyl or cyclohexyl ring. The cyclopropyl ring         as well as the cyclopentyl ring are preferred.     -   The monocyclic or bicyclic carbocyclic aromatic ring A, which         can be substituted in several places, is a carbocyclic or         heterocyclic aryl radical.     -   In the first case, it is, for example, a phenyl or naphthyl         radical, preferably a phenyl radical.     -   As a heterocyclic radical, for example, a monocyclic         heterocyclic radical, for example the thienyl, furyl, pyranyl,         pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,         pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl,         pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl,         or tetrazolyl radical, and specifically all possible isomers         relative to the positions of the heteroatoms, can be used.     -   In terms of R³, an aryl radical is an optionally substituted         phenyl, 1- or 2-naphthyl radical, whereby the phenyl radical is         preferred. Examples of a heteroaryl radical are the 2-, 3- or         4-pyridinyl radical, the 2- or 3-furyl radical, the 2- or         3-thienyl radical, the 2- or 3-pyrrolyl radical, the 2-, 4- or         5-imidazolyl radical, the pyrazinyl radical, the 2-, 4- or         5-pyrimidinyl radical or the 3- or 4-pyridazinyl radical.         -   The number p for the (CH₂)_(p) radical can be a number from             0 to 6, preferably 0 to 2. “Radicals” are defined according             to the invention as all functional groups that are presented             in connection with (CH₂)_(p).

In the case that the compounds of general formula I (B=—CH₂—) are present as salts, this can be, for example, in the form of hydrochloride, sulfate, nitrate, tartrate, citrate, fumarate, succinate or benzoate.

If the compounds according to the invention are present as racemic mixtures, they can be separated into pure, optically active forms according to methods of racemate separation that are familiar to one skilled in the art. For example, the racemic mixtures can be separated into pure isomers by chromatography on an even optically active carrier material (CHIRALPAK AD®). It is also possible to esterify the free hydroxy group in a racemic compound of general formula I with an optically active acid and to separate the diastereomeric esters that are obtained by fractionated crystallization or by chromatography and to saponify the separated esters in each case to form the optically pure isomers. As an optically active acid, for example, mandelic acid, camphorsulfonic acid or tartaric acid can be used.

The compounds that are mentioned below as well as the use thereof are preferred according to the invention:

Racemic or No. Enantiomer R3  1  2  3 rac +−

 4  5  6 rac +−

 7  8  9 rac +−

10 11 12 rac +−

13 14 15 rac +−

16 17 18 rac +−

19 20 21 rac +−

22 23 24 rac +−

25 26 27 rac +−

28 29 30 rac +−

31 32 33 rac +−

34 35 36 rac +−

37 38 39 rac +−

40 41 42 rac +−

43 44 45 rac +−

46 47 48 rac +−

49 50 51 rac +−

52 53 54 rac +−

55 56 57 rac +−

58 59 60 rac +−

Racemic or No. Enantiomer R3 61 62 63 rac +−

64 65 66 rac +−

67 68 69 rac +−

70 71 72 rac +−

73 74 75 rac +−

76 77 78 rac +−

79 80 81 rac +−

82 83 84 rac +−

85 86 87 rac +−

88 89 90 rac +−

91 92 93 rac +−

94 95 96 rac +−

97 98 99 rac +−

100 101 102 rac +−

103 104 105 rac +−

106 107 108 rac +−

109 110 111 rac +−

112 113 114 rac +−

115 116 117 rac +−

118 119 120 rac +−

Racemic or No. Enantiomer R3 121 122 123 rac +−

124 125 126 rac +−

127 128 129 rac +−

130 131 132 rac +−

133 134 135 rac +−

136 137 138 rac +−

139 140 141 rac +−

142 143 144 rac +−

145 146 147 rac +−

148 149 150 rac +−

151 152 153 rac +−

154 155 156 rac +−

157 158 159 rac +−

160 161 162 rac +−

163 164 165 rac +−

166 167 168 rac +−

169 170 171 rac +−

172 173 174 rac +−

175 176 177 rac +−

178 179 180 rac +−

Racemic or No. Enantiomer R3 181 182 183 rac +−

184 185 186 rac +−

187 188 189 rac +−

190 191 192 rac +−

193 194 195 rac +−

196 197 198 rac +−

199 200 201 rac +−

202 203 204 rac +−

205 206 207 rac +−

208 209 210 rac +−

211 212 213 rac +−

214 215 216 rac +−

217 218 219 rac +−

220 221 222 rac +−

223 224 225 rac +−

226 227 228 rac +−

229 230 231 rac +−

232 233 234 rac +−

235 236 237 rac +−

238 239 240 rac +−

Racemic or No. Enantiomer R3 241 242 243 rac +−

244 245 246 rac +−

247 248 249 rac +−

250 251 252 rac +−

253 254 255 rac +−

256 257 258 rac +−

259 260 261 rac +−

262 263 264 rac +−

265 266 267 rac +−

268 269 270 rac +−

271 272 273 rac +−

274 275 276 rac +−

277 278 279 rac +−

280 281 282 rac +−

283 284 285 rac +−

286 287 288 rac +−

289 290 291 rac +−

292 293 294 rac +−

295 296 297 rac +−

298 299 300 rac +−

Racemic or No. Enantiomer R3 301 302 303 rac +−

304 305 306 rac +−

307 308 309 rac +−

310 311 312 rac +−

313 314 315 rac +−

316 317 318 rac +−

319 320 321 rac +−

322 323 324 rac +−

325 326 327 rac +−

328 329 330 rac +−

331 332 333 rac +−

334 335 336 rac +−

337 338 339 rac +−

340 341 342 rac +−

343 344 345 rac +−

346 347 348 rac +−

349 350 351 rac +−

352 353 354 rac +−

355 356 357 rac +−

358 359 360 rac +−

Racemic or No. Enantiomer R3 361 362 363 rac +−

364 365 366 rac +−

367 368 369 rac +−

370 371 372 rac +−

373 374 375 rac +−

376 377 378 rac +−

379 380 381 rac +−

382 383 384 rac +−

385 386 387 rac +−

388 389 390 rac +−

391 392 393 rac +−

394 395 396 rac +−

397 398 399 rac +−

400 401 402 rac +−

403 404 405 rac +−

406 407 408 rac +−

409 410 411 rac +−

412 413 414 rac +−

415 416 417 rac +−

418 419 420 rac +−

Racemic or No. Enantiomer R3 421 422 423 rac +−

424 425 426 rac +−

427 428 429 rac +−

430 431 432 rac +−

433 434 435 rac +−

436 437 438 rac +−

439 440 441 rac +−

442 443 444 rac +−

445 446 447 rac +−

448 449 450 rac +−

451 452 453 rac +−

454 455 456 rac +−

457 458 459 rac +−

460 461 462 rac +−

463 464 465 rac +−

466 467 468 rac +−

469 470 471 rac +−

472 473 474 rac +−

475 476 477 rac +−

478 479 480 rac +−

Racemic or No. Enantiomer R3 481 482 483 rac +−

484 485 486 rac +−

487 488 489 rac +−

490 491 492 rac +−

493 494 495 rac +−

496 497 498 rac +−

499 500 501 rac +−

502 503 504 rac +−

505 506 507 rac +−

508 509 510 rac +−

511 512 513 rac +−

214 515 516 rac +−

517 518 519 rac +−

520 521 522 rac +−

523 524 525 rac +−

526 227 528 rac +−

529 530 531 rac +−

532 533 534 rac +−

535 536 537 rac +−

538 539 540 rac +−

Racemic or No. Enantiomer R3 541 542 543 rac +−

544 545 546 rac +−

547 548 549 rac +−

550 551 552 rac +−

553 554 555 rac +−

556 557 558 rac +−

559 560 561 rac +−

562 563 564 rac +−

565 566 567 rac +−

568 569 570 rac +−

571 572 573 rac +−

574 575 576 rac +−

577 578 579 rac +−

580 581 582 rac +−

583 584 585 rac +−

586 587 588 rac +−

589 590 591 rac +−

592 593 594 rac +−

595 596 597 rac +−

598 599 600 rac +−

Racemic or No. Enantiomer R3 601 602 603 rac +−

604 605 606 rac +−

607 608 609 rac +−

610 611 612 rac +−

613 614 615 rac +−

616 617 618 rac +−

619 620 621 rac +−

622 623 624 rac +−

625 626 627 rac +−

628 629 630 rac +−

631 632 633 rac +−

634 635 636 rac +−

637 638 639 rac +−

640 641 642 rac +−

643 644 645 rac +−

646 647 648 rac +−

649 650 651 rac +−

652 653 654 rac +−

655 656 657 rac +−

658 659 660 rac +−

Racemic or No. Enantiomer R3 661 662 663 rac +−

664 665 666 rac +−

667 668 669 rac +−

670 671 672 rac +−

673 674 675 rac +−

676 677 678 rac +−

679 680 681 rac +−

682 683 684 rac +−

685 686 687 rac +−

688 689 690 rac +−

691 692 693 rac +−

694 695 696 rac +−

697 698 699 rac +−

700 701 702 rac +−

703 704 705 rac +−

706 707 708 rac +−

709 710 711 rac +−

712 713 714 rac +−

715 716 717 rac +−

718 719 720 rac +−

Racemic or No. Enantiomer R3 721 722 723 rac +−

724 725 726 rac +−

727 728 729 rac +−

730 731 732 rac +−

733 734 735 rac +−

736 737 738 rac +−

739 740 741 rac +−

742 743 744 rac +−

745 746 747 rac +−

748 749 750 rac +−

751 752 753 rac +−

754 755 756 rac +−

757 758 759 rac +−

760 761 762 rac +−

763 764 765 rac +−

766 767 768 rac +−

769 770 771 rac +−

772 773 774 rac +−

775 776 777 rac +−

778 779 780 rac +−

Racemic or No. Enantiomer R3 781 782 783 rac +−

784 785 786 rac +−

787 788 789 rac +−

790 791 792 rac +−

793 794 795 rac +−

796 797 798 rac +−

799 800 801 rac +−

802 803 804 rac +−

805 806 807 rac +−

808 809 810 rac +−

811 812 813 rac +−

814 815 816 rac +−

817 818 819 rac +−

820 821 822 rac +−

823 824 825 rac +−

826 827 828 rac +−

829 830 831 rac +−

832 833 834 rac +−

835 836 837 rac +−

838 839 840 rac +−

Racemic or No. Enantiomer R3 841 842 843 rac +−

844 845 846 rac +−

847 848 849 rac +−

850 851 852 rac +−

853 854 855 rac +−

856 857 858 rac +−

859 860 861 rac +−

862 863 864 rac +−

865 866 867 rac +−

868 869 870 rac +−

871 872 873 rac +−

874 875 876 rac +−

877 878 879 rac +−

880 881 882 rac +−

883 884 885 rac +−

886 887 888 rac +−

889 890 891 rac +−

892 893 894 rac +−

895 896 897 rac +−

898 899 900 rac +−

Racemic or No. Enantiomer R3 901 902 903 rac +−

904 905 906 rac +−

907 908 909 rac +−

910 911 912 rac +−

913 914 915 rac +−

916 917 918 rac +−

919 920 921 rac +−

922 923 924 rac +−

925 926 927 rac +−

928 929 930 rac +−

931 932 933 rac +−

934 935 936 rac +−

937 938 939 rac +−

940 941 942 rac +−

943 944 945 rac +−

946 947 948 rac +−

949 950 951 rac +−

952 953 954 rac +−

955 956 957 rac +−

958 959 960 rac +−

Racemic or No. Enantiomer R3 961 962 963 rac +−

964 965 966 rac +−

967 968 969 rac +−

970 971 972 rac +−

973 974 975 rac +−

976 977 978 rac +−

979 980 981 rac +−

982 983 984 rac +−

985 986 987 rac +−

988 989 990 rac +−

991 992 993 rac +−

994 995 996 rac +−

997 998 999 rac +−

1000 1001 1002 rac +−

1003 1004 1005 rac +−

1006 1007 1008 rac +−

1009 1010 1011 rac +−

1012 1013 1014 rac +−

1015 1016 1017 rac +−

1018 1019 1020 rac +−

Racemic or No. Enantiomer R3 1021 1022 1023 rac +−

1024 1025 1026 rac +−

1027 1028 1029 rac +−

1030 1031 1032 rac +−

1033 1034 1035 rac +−

1036 1037 1038 rac +−

1039 1040 1041 rac +−

1042 1043 1044 rac +−

1045 1046 1047 rac +−

1048 1049 1050 rac +−

1051 1052 1053 rac +−

1054 1055 1056 rac +−

1057 1058 1059 rac +−

1060 1061 1062 rac +−

1063 1064 1065 rac +−

1066 1067 1068 rac +−

1069 1070 1071 rac +−

1072 1073 1074 rac +−

1075 1076 1077 rac +−

1078 1079 1080 rac +−

Racemic or No. Enantiomer R3 1081 1082 1083 rac +−

1084 1085 1086 rac +−

1087 1088 1089 rac +−

1090 1091 1092 rac +−

1093 1094 1095 rac +−

1096 1097 1098 rac +−

1099 1100 1101 rac +−

1102 1103 1104 rac +−

1105 1106 1107 rac +−

1108 1109 1110 rac +−

1111 1112 1113 rac +−

1114 1115 1116 rac +−

1117 1118 1119 rac +−

1120 1121 1122 rac +−

1123 1124 1125 rac +−

1126 1127 1128 rac +−

1129 1130 1131 rac +−

1132 1133 1134 rac +−

1135 1136 1137 rac +−

1138 1139 1140 rac +−

Racemic or No. Enantiomer R3 1141 1142 1143 rac +−

1144 1145 1146 rac +−

1147 1148 1149 rac +−

1150 1151 1152 rac +−

1153 1154 1155 rac +−

1156 1157 1158 rac +−

1159 1160 1161 rac +−

1162 1163 1164 rac +−

1165 1166 1167 rac +−

1168 1169 1170 rac +−

1171 1172 1173 rac +−

1174 1175 1176 rac +−

1177 1178 1179 rac +−

1180 1181 1182 rac +−

1183 1184 1185 rac +−

1186 1187 1188 rac +−

1189 1190 1191 rac +−

1192 1193 1194 rac +−

1195 1196 1197 rac +−

1198 1199 1200 rac +−

Racemic or No. Enantiomer R3 1201 1202 1203 rac +−

1204 1205 1206 rac +−

1207 1208 1209 rac +−

1210 1211 1212 rac +−

1213 1214 1215 rac +−

1216 1217 1218 rac +−

1219 1220 1221 rac +−

1222 1223 1224 rac +−

1225 1226 1227 rac +−

1228 1229 1230 rac +−

1231 1232 1233 rac +−

1234 1235 1236 rac +−

1237 1238 1239 rac +−

1240 1241 1242 rac +−

1243 1244 1245 rac +−

1246 1247 1248 rac +−

1249 1250 1251 rac +−

1252 1253 1254 rac +−

1255 1256 1257 rac +−

1258 1259 1260 rac +−

Racemic or No. Enantiomer R3 1261 1262 1263 rac +−

1264 1265 1266 rac +−

1267 1268 1269 rac +−

1270 1271 1272 rac +−

1273 1274 1275 rac +−

1276 1277 1278 rac +−

1279 1280 1281 rac +−

1282 1283 1284 rac +−

1285 1286 1287 rac +−

1288 1289 1290 rac +−

1291 1292 1293 rac +−

1294 1295 1296 rac +−

1297 1298 1299 rac +−

1300 1301 1302 rac +−

1303 1304 1305 rac +−

1306 1307 1308 rac +−

1309 1310 1311 rac +−

1312 1313 1314 rac +−

1315 1316 1317 rac +−

1318 1319 1320 rac +−

Racemic or No. Enantiomer R3 1321 1322 1323 rac +−

1324 1325 1326 rac +−

1327 1328 1329 rac +−

1330 1331 1332 rac +−

1333 1334 1335 rac +−

1336 1337 1338 rac +−

1339 1340 1341 rac +−

1342 1343 1344 rac +−

1345 1346 1347 rac +−

1348 1349 1350 rac +−

1351 1352 1353 rac +−

1354 1355 1356 rac +−

1357 1358 1359 rac +−

1360 1361 1362 rac +−

1363 1364 1365 rac +−

1366 1367 1368 rac +−

1369 1370 1371 rac +−

1372 1373 1374 rac +−

1375 1376 1377 rac +−

1378 1379 1380 rac +−

Racemic or No. Enantiomer R3 1381 1382 1383 rac +−

1384 1385 1386 rac +−

1387 1388 1389 rac +−

1390 1391 1392 rac +−

1393 1394 1395 rac +−

1396 1397 1398 rac +−

1399 1400 1401 rac +−

1402 1403 1404 rac +−

1405 1406 1407 rac +−

1408 1409 1410 rac +−

1411 1412 1413 rac +−

1414 1415 1416 rac +−

1417 1418 1419 rac +−

1420 1421 1422 rac +−

1423 1424 1425 rac +−

1426 1427 1428 rac +−

1429 1430 1431 rac +−

1432 1433 1434 rac +−

1435 1436 1437 rac +−

1438 1439 1440 rac +−

Racemic or No. Enantiomer R3 1441 1442 1443 rac +−

1444 1445 1446 rac +−

1447 1448 1449 rac +−

1450 1451 1452 rac +−

1453 1454 1455 rac +−

1456 1457 1458 rac +−

1459 1460 1461 rac +−

1462 1463 1464 rac +−

1465 1466 1467 rac +−

1468 1469 1470 rac +−

1471 1472 1473 rac +−

1474 1475 1476 rac +−

1477 1478 1479 rac +−

1480 1481 1482 rac +−

1483 1484 1485 rac +−

1486 1487 1488 rac +−

1489 1490 1491 rac +−

1492 1493 1494 rac +−

1495 1496 1497 rac +−

1498 1499 1500 rac +−

Racemic or No. Enantiomer R3 1501 1502 1503 rac +−

1504 1505 1506 rac +−

1507 1508 1509 rac +−

1510 1511 1512 rac +−

1513 1514 1515 rac +−

1516 1517 1518 rac +−

1519 1520 1521 rac +−

1522 1523 1524 rac +−

1525 1526 1527 rac +−

1528 1529 1530 rac +−

1531 1532 1533 rac +−

1534 1535 1536 rac +−

1537 1538 1539 rac +−

1540 1541 1542 rac +−

1543 1544 1545 rac +−

1546 1547 1548 rac +−

1549 1550 1551 rac +−

1552 1553 1554 rac +−

1555 1556 1557 rac +−

1558 1559 1560 rac +−

Racemic or No. Enantiomer R3 1561 1562 1563 rac +−

1564 1565 1566 rac +−

1567 1568 1569 rac +−

1570 1571 1572 rac +−

1573 1574 1575 rac +−

1576 1577 1578 rac +−

1579 1580 1581 rac +−

1582 1583 1584 rac +−

1585 1586 1587 rac +−

1588 1589 1590 rac +−

1591 1592 1593 rac +−

1594 1595 1596 rac +−

1597 1598 1599 rac +−

1600 1601 1602 rac +−

1603 1604 1605 rac +−

1606 1607 1608 rac +−

1609 1610 1611 rac +−

1612 1613 1614 rac +−

1615 1616 1617 rac +−

1618 1619 1620 rac +−

Biological Characterization of the Compounds According to the Invention

The identification of progesterone receptor modulators can be performed using simple methods, test programs that are known to one skilled in the art. To this end, for example, a compound that is to be tested can be incubated together with a gestagen in a test system for progesterone receptors, and it can be examined whether the progesterone-mediated action in this test system is altered in the presence of modulators.

The substances of general formula I according to the invention were tested in the following models:

Progesterone Receptor Binding Test

Measurement of the Receptor Binding Affinity:

The receptor binding affinity was determined by competitive binding of a specifically binding ³H-labeled hormone (tracer) and the compound to be tested on receptors in the cytosol from animal target organs. In this case, receptor saturation and reaction equilibrium were sought.

The tracers and increasing concentrations of the compound to be tested (competitor) were co-incubated with the receptor-containing cytosol fraction at 0-4° C. over 18 hours. After separation of the unbonded tracer with carbon-dextran suspension, the receptor-bonded tracer portion was measured for each concentration, and the IC₅₀ was determined from the concentration sequence. As a quotient of the IC₅₀ values of the reference substance and the compound to be tested (×100%), the relative molar binding affinity (RBA) was calculated (RBA of the reference substance=100%).

For the receptor types, the following incubation conditions were selected:

Progesterone Receptor:

Uterus cytosol of the estradiol-primed rabbit, homogenized in TED buffer (20 mmol of Tris/HCl, pH 7.4; 1 mmol of ethylenediamine tetraacetate, 2 mmol of dithiothreitol) with 250 mmol of saccharose; stored at −30° C. Tracer: ³H—ORG 2058, 5 nmol; reference substance: progesterone.

Glucocorticoid Receptor:

Thymus cytosol of the adrenalectomized rat, thymi stored at −30° C.; buffer: TED. Tracer: ³H-Dexamethasone, 20 nmol; reference substance: dexamethasone.

The relative receptor binding affinities (RBA values) of the compounds of general formula (I) according to the invention on the progesterone receptor are between 3 and 100% relative to the progesterone. On the glucocorticoid receptor, the RBA values are in the range of 3 to 30% relative to dexamethasone.

The compounds according to the invention accordingly have a high affinity to the progesterone receptor but only a low affinity to the glucocorticoid receptor.

Antagonism of Progesterone Receptor PR-B

The transactivation assay is performed as described in WO 02/054064.

Agonism of Progesterone Receptor PR-B

The transactivation assay is performed as described in Fuhrmann et al. (Fuhrmann, U.; Hess-Stump, H.; Cleve, A.; Neef, G.; Schwede, W.; Hoffmann, J.; Fritzemeier, K.-H., Chwalisz, K.; Journal of Medicinal Chem., 43, 26, 2000, 5010-5016). Antagonistic activity Agonistic activity No. IC₅₀ [nM] Efficacy [%] EC₅₀ [nM] Efficacy [%]  9 3 96 n.b. 3 13 3 92 n.b. 7  3b 0.4 97 n.b. 2  7 4 82 2 11 Dosage

For use according to the invention, the progesterone receptor modulators can be administered orally, enterally, parenterally or transdermally.

In general, satisfactory results can be expected in the treatment of the above-mentioned indications if the daily doses encompass a range of 1 μg to 500 mg of the compound according to the invention.

Suitable dosages of the compounds according to the invention in humans for the treatment of endometriosis, leiomyomas of the uterus and dysfunctional bleeding as well as for use in birth control as well as for hormone replacement therapy are 50 μg to 500 mg per day, depending on age and constitution of the patient, whereby the necessary daily dose can be administered one or more times.

For treatment of breast cancer, the dosage range for the compounds according to the invention comprises 10 mg to 1000 mg daily.

The formulation of the pharmaceutical preparations based on the new compounds is carried out in a way that is known in the art, by the active ingredient being processed with the vehicles, fillers, substances that influence decomposition, binding agents, moisturizers, lubricants, absorbents, diluents, flavoring correctives, dyes, etc., that are commonly used in galenicals and being converted into the desired form of administration. In this case, reference is made to Remington's Pharmaceutical Science, 15^(th) Ed. Mack Publishing Company, East Pennsylvania (1980).

For oral administration, in particular tablets, film tablets, coated tablets, capsules, pills, powders, granulates, lozenges, suspensions, emulsions or solutions are suitable.

For parenteral administration, injection and infusion preparations are possible.

For intraarticulate injection, correspondingly prepared crystal suspensions can be used.

For intramuscular injection, aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.

For rectal administration, the new compounds can be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments both for systemic therapy and for local therapy.

In addition, agents for vaginal application can also be mentioned as preparations.

For pulmonary administration of the new compounds, the latter can be used in the form of aerosols and inhalants.

For transdermal administration, patches are possible, or for topical application, formulations in gels, ointments, fatty ointments, creams, pastes, powders, milk and tinctures are possible. The dosage of the compounds of general formula I should be 0.01%-20% in these preparations to achieve an adequate pharmacological action.

Corresponding tablets can be obtained by, for example, mixing active ingredient with known adjuvants, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, explosives such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents for achieving a depot effect such as carboxylpolymethylene, carboxylmethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.

Accordingly, coated tablets can be produced by coating cores, produced analogously to the tablets, with agents that are commonly used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. In this case, the coated tablet shell can also consist of several layers, whereby the adjuvants that are mentioned above in the tablets can be used.

Solutions or suspensions of the compounds of general formula I according to the invention can contain additional taste-improving agents such as saccharine, cyclamate or sugar, as well as, e.g., flavoring substances, such as vanilla or orange extract. In addition, they can contain suspending adjuvants such as sodium carboxy methyl cellulose or preservatives such as p-hydroxybenzoates.

The capsules that contain compounds of general formula I can be produced by, for example, the compound(s) of general formula I being mixed with an inert vehicle such as lactose or sorbitol and encapsulated in gelatin capsules.

Suitable suppositories can be produced by, for example, mixing with vehicles that are provided for this purpose, such as neutral fats or polyethylene glycol, or derivatives thereof.

The compounds of general formula (I) according to the invention or their pharmaceutically acceptable salts can be used based on their antagonistic or partial agonistic action for the production of a pharmaceutical agent, in particular for treatment and prophylaxis of gynecological diseases, such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhea. In addition, they can be used to counteract hormonal irregularities, to trigger menstruation and alone or in combination with prostaglandins and/or oxytocin to induce birth.

In addition, the compounds of general formula (I) according to the invention or their pharmaceutically acceptable salts are suitable for the production of preparations for contraception for women (see also WO 93/23020, WO 93/21927).

In addition, the compounds according to the invention or their pharmaceutically acceptable salts can be used alone or in combination with a Selective Estrogen Receptor Modulator (SERM) for female hormone replacement therapy.

In addition, the above-mentioned compounds exert an antiproliferative action in hormone-dependent tumors. They are therefore suitable for the therapy of hormone-dependent carcinomas, such as, for example, for breast, prostate or endometrial carcinomas.

The compounds according to the invention or their pharmaceutically acceptable salts can be used for the treatment of hormone-dependent carcinomas, both in first-line therapy and in second-line therapy, in particular after tamoxifen failure.

The compounds of general formula (I) according to the invention that have an antagonistic or partial agonistic action or their pharmaceutically acceptable salts can also be used in combination with compounds that have an antiestrogenic action (estrogen receptor antagonists or aromatase inhibitors) or Selective Estrogen Receptor Modulators (SERM) for the production of pharmaceutical preparations for treating hormone-dependent tumors. For the treatment of endometriosis or leiomyomas of the uterus, the compounds according to the invention can also be used in combination with SERMs or an antiestrogen (estrogen receptor antagonists or aromatase inhibitors). In the treatment of hormone-dependent tumors, the progesterone receptor modulator and the antiestrogen (estrogen receptor antagonists or aromatase inhibitors) or the SERM can be provided for simultaneous or else for sequential administration. In sequential administration, preferably first the antiestrogen (estrogen receptor antagonists or aromatase inhibitor) or SERM is administered, and then the progesterone receptor modulator is administered.

In this case, in the combination with the nonsteroidal progesterone receptor modulators according to the invention, for example, the following antiestrogens (estrogen receptor antagonists or aromatase inhibitors) or SERMs are considered:

tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulfinyl]-pentyloxy}phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7alpha-[9-(4,4,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17-beta-diol), 11beta-fluoro-7alpha-[5-(methyl {3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17beta-diol (WO98/07740), 11beta-fluoro-7alpha-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-triene-3,17beta-diol (WO 99/33855), 11 beta-fluoro-17alpha-methyl-7alpha-{5-[methyl(8,8,9,9,9-pentafluorononyl)-amino]pentyl}estra-1,3,5(10)-triene-3,17beta-diol (WO 03/045972), clomifene, raloxifene as well as other antiestrogenically active compounds, and aromatase inhibitors, such as, for example, fadrozole, formestane, letrozole, anastrozole or atamestane.

Finally, this invention also relates to the use of the compounds of general formula I, optionally together with an antiestrogen or SERM, for the production of a pharmaceutical agent.

This invention also relates to pharmaceutical compositions that contain at least one compound according to the invention, optionally in the form of a pharmaceutically/pharmacologically compatible salt, without or together with pharmaceutically compatible adjuvants and/or vehicles.

These pharmaceutical compositions and pharmaceutical agents can be provided for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration. In addition to commonly used vehicles and/or diluents, they contain at least one compound according to the invention.

The pharmaceutical agents of the invention are produced in a known way with the commonly used solid or liquid vehicles or diluents and the usually used pharmaceutical-technical adjuvants corresponding to the desired type of administration with a suitable dosage. The preferred preparations exist in a dispensing form that is suitable for oral administration. Such dispensing forms are, for example, tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions or else depot forms.

The pharmaceutical compositions that contain at least one of the compounds according to the invention are preferably administered orally.

Parenteral preparations, such as injection solutions, are also considered.

In addition, for example, suppositories and agents for vaginal application can also be mentioned as preparations.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.

The following examples are used for a more detailed explanation of the subject of the invention, without intending that it be limited to these examples.

The production of the starting compound 5-{3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxopropionylamino}phthalide is described in Patent WO 200375915, and the production of 5-{3-[1-phenyl-cyclopropyl]-2-oxopropionylamino}phthalide is described in WO 9854159.

rac-5-{2-Ethinyl-2-hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-propionylamino}phthalide 1

Ethinyl magnesium bromide (6 ml, 0.5 M in tetrahydrofuran) was added to an ice-cold solution that consists of 5-{3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxopropionylamino}phthalide (632 mg) in THF (4 ml). The reaction solution under argon was allowed to come to room temperature within 3 hours. Then, the reaction mixture was poured into ice-cold, saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried on sodium sulfate. The crude product that is obtained was chromatographed on silica gel. 2.2 g of product was obtained.

¹H-NMR (ppm, CDCl₃, 400 MHz): 0.83 (1H), 0.92-1.10 (2H), 2.37 (1H), 2.56 (1H), 2.59 (1H), 3.10 (1H), 5.28 (2H), 7.02 (1H), 7.31 (1H), 7.37 (1H), 7.58 (1H), 7.86 (1H), 7.94 (1H), 8.70 (1H).

rac-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-propinyl-propionylamino}phthalide 2

Analogously to Example 1, 145 mg of product was obtained from 1-propinylmagnesium bromide (2 ml of 0.5 M solution in tetrahydrofuran) and 210 mg of 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one.

¹H-NMR (ppm, CDCl₃, 400 MHz): 0.86 (1H), 0.90-1.05 (3H), 1.72 (3H), 2.35 (1H), 2.49 (1H), 2.96 (1H), 5.27 (2H), 7.03 (1H), 7.30 (1H), 7.36 (1H), 7.58 (1H), 7.85 (1H), 7.98 (1H), 8.73 (1H).

(+)-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-phenyl-propionylamino}phthalide 3a and (−)-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-(phenylethinyl)-propionylamino}phthalide 3b

n-Butyllithium (625 μl, 1.6 M in hexane) was added at −78° C. to a solution of 110 μl of phenylacetylene in tetrahydrofuran. Stirring was allowed to continue at this temperature for 30 minutes, and then a solution of 5-{3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxopropionylamino}phthalide (210 mg) in 5 ml of tetrahydrofuran was added in drops. Then, it was allowed to come to 23° C. over about 3 hours and then stirred for 10 more hours. Then, the reaction mixture was poured into ice-cold, saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried on sodium sulfate. The crude product was chromatographed on silica gel. The racemic mixture obtained was then separated by preparative chiral HPLC (Chiralpak AD column, 250×10 mm) into enantiomers 3a (46 mg) and 3b (47 mg).

3a and 3b:

¹H-NMR (ppm, CDCl₃, 300 MHz): 0.88 (1H), 0.95-1.11 (3H), 2.46 (1H), 2.65 (1H), 3.10 (1H), 5.27 (2H), 7.00 (1H), 7.24-7.42 (7H), 7.61 (1H), 7.84 (1H), 7.98 (1H), 8.80 (1H).

3a: [α]^(D) ₂₀: +12.9° (CHCl₃, 1.06 g/100 ml; λ=589 nM)

3b: [α]^(D) ₂₀: −14.4° (CHCl₃, 1.03 g100 ml; λ=589 nM)

Analogously to Example 3, compounds 4 and 5 were produced from 5-{3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxopropionylamino}phthalide and the respective lithium aryl acetylide.

rac-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-[(4-trifluoromethylphenyl)ethinyl]propionylamino}phthalide 4

¹H-NMR (ppm, CDCl₃, 300 MHz): 0.92 (1H), 0.99-1.16 (3H), 2.55 (1H), 2.68 (1H), 3.27 (1H), 5.30 (2H), 7.03 (1H), 7.30-7.52 (4H), 7.55-7.62 (2H), 6.67 (1H), 7.99 (1H), 8.03 (1H), 8.84 (1H).

(+)-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluormethylphenyl)-cyclopropyl]-2-[(4-trifluormethylphenyl)ethinyl]propionylamino}phthalide 4a and (−)-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluormethylphenyl)-cyclopropyl]-2-[(4-trifluormethylphenyl)ethinyl]propionylamino}phthalide 4b

The racemic mixture (150 mg) which was described in example 4 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 4a (51 mg) and 4b (62 mg).

4a: [α]^(D) ₂₀: +6.3° (CHCl₃, 1.07 g/100 ml; λ=589 nM)

4b: [α]^(D) ₂₀: −5.3° (CHCl₃, 1.09 g100 ml; λ=589 nM)

rac-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-[(4-methylphenyl)ethinyl]propionylamino}phthalide 5

¹H-NMR (ppm, CDCl₃, 300 MHz): 0.87 (1H), 0.93-1.15 (3H), 2.38 (3H), 2.45 (1H), 2.66 (1H), 3.11 (1H), 5.25 (2H), 6.99 (1H), 7.10 (2H), 7.18-7.38 (4H), 7.61 (1H), 7.86 (1H), 8.00 (1H), 8.80 (1H).

(+)-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-[(4-methylphenyl)ethinyl]propionylamino}phthalide 5a and (−)-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-[(4-methylphenyl)ethiny]propionylamino}phthalide 5b

The racemic mixture (109 mg) which was described in example 5 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 5a (41 mg) and 5b (28 mg).

5a: [α]^(D) ₂₀: +14.8° (CHCl₃, 1.07 g/100 ml; λ=589 nM)

5b: [α]^(D) ₂₀: −16.3° (CHCl₃, 1.13 g100 ml; λ=589 nM)

rac-5-{2-[(4-Acetoxyphenyl)ethinyl]-2-hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-propionylamino}phthalide 6

A suspension of the compound (104 mg) described under Example 1, triphenylphosphine (12.2 mg), copper iodide (8.9 mg), 4-iodophenyl acetate (92 mg), palladium acetate (5.3 mg) in THF (5 ml) and triethylamine (5 ml) was reacted for 1 hour in an ultrasound bath at 25° C. under argon. Then, it was poured into saturated, aqueous ammonium chloride solution. It was extracted with ethyl acetate and washed with water and saturated sodium chloride solution. The combined organic phases were dried on sodium sulfate. After column chromatography of the crude product on silica gel, 55 mg of product was obtained.

¹H-NMR (ppm, CDCl₃, 400 MHz): 0.88 (1H), 0.95-1.10 (3H), 2.29 (3H), 2.45 (1H), 2.63 (1H), 3.17 (1H), 5.29 (2H), 6.97-7.07 (3H), 7.28-7.37 (4H), 7.60 (1H), 7.84 (1H), 7.98 (1H), 8.80 (1H).

rac-5-{2-Hydroxy-2-[(4-hydroxyphenyl)ethinyl]-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-propionylamino}phthalide 7

A solution of the compound described under 6 (45 mg) in 5 ml of methanol was mixed with sodium bicarbonate (130 mg). Stirring was continued for 2 more hours at 23° C. Then, the reaction mixture was diluted with ethyl acetate. Then, it was washed twice with saturated sodium chloride solution. After drying on sodium sulfate, the crude product was purified on silica gel by column chromatography. 38 mg of product was obtained.

¹H-NMR (ppm, CDCl₃, 300 MHz): 0.87 (1H), 0.92-1.11 (3H), 2.43 (1H), 2.64 (1H), 3.11 (1H), 5.27 (2H), 5.67 (1H), 6.73 (2H), 6.9.8 (1H), 7.14 (2H), 7.28-7.38 (2H), 7.60 (1H), 7.85 (1H), 7.97 (1H), 8.84 (1H).

rac-5-{2-[(4-Carboxyphenyl)ethinyl]-2-hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-propionylamino}phthalide 8

Analogously to Example 6, compound 8 was produced from the compound described under Example 1 and 4-iodobenzoic acid.

¹H-NMR (ppm, CDCl₃/MeOD (5%), 400 MHz): 0.82 (1H), 0.89-1.05 (3H), 2.37 (1H), 2.65 (1H), 5.24 (2H), 6.97 (1H), 7.35 (1H), 7.44 (2H), 7.50-7.65 (2H), 7.72 (1H), 7.80 (1H), 7.92 (2H).

rac-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-(pentin-1-yl)-propionylamino}phthalide 9

A solution that consists of 1-pentyne (0.94 ml) in THF (9 ml) was mixed at −78° C. with nBuLi (0.6 ml, 1.6 M in hexane). It was allowed to stir for 30 minutes at −78° C., and then a solution of 5-{3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxopropionylamino}phthalide (200 mg) in 3 ml of tetrahydrofuran was added. Then, it was allowed to come to 23° C. over about 3 hours, and it was stirred for 10 more hours at this temperature. Then, the reaction mixture was poured into ice-cold, saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried on sodium sulfate. The crude product was chromatographed on silica gel. 130 mg of product was obtained.

¹H-NMR (ppm, CDCl₃, 400 MHz): 0.82 (1H), 0.92-1.07 (6H), 1.45 (2H), 2.08 (2H), 2.30 (1H), 2.53 (1H), 2.83 (1H), 5.27 (2H), 7.02 (1H), 7.29 (1H), 7.36 (1H), 7.57 (1H), 7.84 (1H), 7.96 (1H), 8.72 (1H).

(+)-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-(pentin-1-yl)-propionylamino}phthalide 9a and (−)-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-(pentin-1-yl)-propionylamino}phtlialide 9b

The racemic mixture (120 mg) which was described in example 9 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 9a (46 mg) and 9b (47 mg).

9a: [α]^(D) ₂₀: +10.9° (CHCl₃, 1.01 g/100 ml; λ=589 nM)

9b: [α]^(D) ₂₀: −10.6° (CHCl₃, 1.08 g100 ml; λ=589 nM)

rac-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-(hexin-1-yl)-propionylamino}phthalide 10

Compound 10 was synthesized analogously to Example 9.

¹H-NMR (ppm, CDCl₃, 400 MHz): 0.80-1.06 (7H), 1.30-1.50 (2H), 1.59 (2H), 2.10 (2H), 2.30 (1H), 2.52 (1H), 2.82 (1H), 5.28 (2H), 7.02 (1H), 7.30 (1H), 7.36 (1H), 7.57 (1H), 7.84 (1H), 7.95 (1H), 8.72 (1H).

rac-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-[(4-hydroxy)butin-1-yl]-propionylamino}phthalide 11

Stage A: Reaction of 4-(tert-butyldimethylsilyloxo)but-1-yne (175 mg), nBuLi (0.59 ml, 1.6 M in hexane) 5-{3-[1-(2-Fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxopropionylamino}-phthalide (200 mg) in tetrahydrofuran analogously to the process described under Example 9 yielded 165 mg of product.

Stage B: The product obtained under stage A (160 mg) was dissolved in 5 ml of tetrahydrofuran. At 0° C., 270 μl of a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran was added and stirred for one hour at 0° C. and for another 2 hours at 23° C. Then, the reaction mixture was poured into saturated, aqueous sodium bicarbonate solution. It was extracted several times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried on sodium sulfate. After column chromatography on silica gel, 77 mg of product was obtained.

¹H-NMR (ppm, CDCl₃, 400 MHz): 0.83 (1H), 0.90-1.03 (3H), 2.20-2.40 (3H), 2.50 (1H), 3.39 (1H), 3.68 (2H), 5.25 (2H), 7.01 (1H), 7.32 (2H), 7.57 (1H), 7.82 (1H), 7.93 (1H), 8.91 (1H).

Analogously to Example 11, compounds 12 and 13 were produced from 5-{3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxopropionylamino}phthalide:

rac-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-[(5-hydroxy)pentin-1-yl]-propionylamino}phthalide 12

¹H-NMR (ppm, CDCl₃, 400 MHz): 0.83 (1H), 0.90-1.03 (3H), 1.70 (2H), 2.24 (2H), 2.33 (1H), 2.50 (1H), 3.09 (1H), 3.71 (2H), 5.26 (2H), 7.02 (1H), 7.35 (2H), 7.57 (1H), 7.83 (1H), 7.97 (1H), 8.82 (1H).

rac-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-[(3-hydroxy)propin-1-yl]-propionylamino}phthalide 13

¹H-NMR (ppm, CDC₃, 400 MHz): 0.84 (1H), 0.90-1.03 (3H), 2.37 (1H), 2.52 (1H), 3.25 (1H), 4.17 (2H), 5.27 (2H), 7.02 (1H), 7.30-7.40 (2H), 7.58 (1H), 7.83 (1H), 7.91 (1H), 8.77 (1H).

(+)-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-[(3-hydroxy)propin-1-yl]-propionylamino}phthalide 13a and (−)-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-[(3-hydroxy)propin-1-yl]-propionylamino}phthalide 13b

The racemic mixture (80 mg) which was described in example 13 was separated by preparative chiral HPLC (column Chiralpak AD 250×10 mm) into the enantiomers 13a (35 mg) and 13b (37 mg).

13a: [α]^(D) ₂₀: +28.3° (CHCl₃, 1.01 g/100 ml; λ=589 nM)

13b: [α]^(D) ₂₀: −29.3° (CHCl₃, 1.08 g100 ml; λ=589 nM)

rac-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-[(4-hydroxy-3-methyl)butin-1-yl]-propionylamino}phthalide 14

Stage A: Analogously to Example 11, 300 mg of 5-{3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxopropionylamino}phthalide and 282 mg of tert-butyl-(1,1-dimethylprop-2-ynyl-oxy)-dimethylsilane are reacted. 15 mg of product A is obtained.

Stage B: 70 mg of the compound that is obtained under A was dissolved in 1 ml of dichloromethane. 650 μl of trifluoroacetic acid (20% in dichloromethane) was added at 0° C., and it was stirred for 3.5 hours at 0° C. Then, it was evaporated to the dry state in a vacuum, and the residue was purified by column chromatography on silica gel. 27 mg of product was obtained.

¹H-NMR (ppm, CDCl₃, 400 MHz): 0.82 (1H), 0.90-1.00 (2H), 1.04 (1H), 1.47 (6H), 2.28 (1H), 2.58 (1H), 3.08 (1H), 5.27 (2H), 7.03 (1H), 7.30 (1H), 7.36 (1H), 7.59 (1H), 7.83 (1H), 7.91 (1H), 8.78 (1H).

rac-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-(2-(tert-butylcarboxy)ethin-1-yl)-propionylamino}phthalide 15

Compound 15 was synthesized analogously to Example 9.

¹H-NMR (ppm, CDCl₃, 400 MHz): 0.87 (1H), 0.93-1.05 (3H), 1.46 (9H), 2.42 (1H), 2.59 (1H), 3.39 (1H), 5.28 (2H), 7.03 (1H), 7.30-7.42 (2H), 7.57 (1H), 7.85 (1H), 7.92 (1H), 8.68 (1H).

rac-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-(2-carboxyethin-1-yl)-propionylamino}phthalide 16

50 mg of the compound that is described under Example 15 was dissolved in 5 ml of dichloromethane. 100 μl of trifluoroacetic acid was added, and it was stirred for 12 more hours at 23° C. Then, it was evaporated to the dry state in a vacuum, and the residue was purified by column chromatography on silica gel. 36 mg of product was obtained.

¹H-NMR (ppm, DMSO-D₆, 300 MHz): 0.48 (1H), 0.78 (1H), 0.86 (1H), 1.09 (1H), 1.73 (1H), 2.89 (1H), 5.27 (2H), 6.62 (1H), 7.13 (1H), 7.31 (1H), 7.41 (1H), 7.53 (1H), 7.62 (1H), 7.68 (1H), 9.85 (1H).

Analogously to Example 3, compound 17 was produced from 5-{3-[1-phenyl-cyclopropyl]-2-oxopropionylamino}phthalide:

rac-5-{2-Hydroxy-3-[1-phenyl-cyclopropyl]-2-(phenyl-ethinyl)propionylamino}-phthalide 17

¹H-NMR (ppm, CDCl₃, 400 MHz): 0.78 (1H), 0.90 (1H), 1.10-1.21 (2H), 2.38 (1H), 2.72 (1H), 2.77 (1H), 5.28 (2H), 7.18 (1H), 7.25-7.42 (6H), 7.41-7.52 (4H), 7.82 (1H), 8.06 (1H), 8.79 (1H).

The entire disclosures of all applications, patents and publications, cited herein and of corresponding German application No. 102005030294.7, filed Jun. 24, 2005, and U.S. Provisional Application Ser. No. 60/693,404, filed Jun. 24, 2005 are incorporated by reference herein.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. 

1. Compounds of general formula I

in which R¹ and R², independently of one another, mean a hydrogen atom, a straight or nonstraight, branched or unbranched C₁-C₅-alkyl group, also together with the C atom of the chain forming a ring with a total of 3-7 members, R³ means a radical C≡C—R^(a), whereby R^(a) means a hydrogen or a C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkinyl, C₃-C₁₀-cycloalkyl, or heterocycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, or an aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, K is a cyano, halogen, hydroxy, nitro, —C(O)R^(b), CO₂R^(b), —O—R^(b), —S—R^(b), SO₂NR^(c)R^(d), —C(O)—NR^(c)R^(d), —OC(O)—NR^(c)R^(d), or —C═NOR^(b)—NR^(c)R^(d) or a C₃-C₁₀-cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with M, heterocycloalkyl, or aryl or heteroaryl that optionally is substituted in one or more places with L, L means C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkinyl, C₁-C₆-perfluoroalkyl, C₁-C₆-perfluoroalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkoxy, (CH₂)_(p)—C₃-C₁₀-cycloalkyl, (CH₂)_(p)-heterocycloalkyl, (CH₂)_(p)CN, (CH₂)_(p)Hal, (CH₂)_(p)NO₂, (CH₂)_(p)—C₆-C₁₂-aryl, (CH₂)_(p)-heteroaryl, —(CH₂)_(p)PO₃(R^(b))₂, —(CH₂)_(p)NR^(c)R^(d), —(CH₂)_(p)NR^(e)COR^(b), —(CH₂)_(p)NR^(e)CSR^(b), —(CH₂)_(p)NR^(e)S(O)R^(b), —(CH₂)_(p)NR^(e)S(O)₂R^(b), —(CH₂)_(p)NR^(e)CONR^(c)R^(d), —(CH₂)_(p)NR^(e)COOR^(b), —(CH₂)_(p)NR^(e)C(NH)NR^(c)R^(d), —(CH₂)_(p)NR^(e)CSNR^(c)R^(d), —(CH₂)_(p)NR^(e)S(O)NR^(c)R^(d), —(CH₂)_(p)NR^(e)S(O)₂NR^(c)R^(d), —(CH₂)_(p)COR^(b), —(CH₂)_(p)CSR^(b), —(CH₂)_(p)S(O)R^(b), —(CH₂)_(p)S(O)(NH)R^(b), —(CH₂)_(p)S(O)₂R^(b), —(CH₂)_(p)S(O)₂NR^(c)R^(d), —(CH₂)_(p)SO₂OR^(b), —(CH₂)_(p)CO₂R^(b), —(CH₂)_(p)CONR^(c)R^(d), —(CH₂)_(p)CSNR^(c)R^(d), —(CH₂)_(p)OR^(b), —(CH₂)_(p)SR^(b), —(CH₂)_(p)CR^(b)(OH)—R^(e), —(CH₂)_(p)—C═NOR^(b), —O—(CH₂)_(n)—O—, —O—(CH₂), —CH₂—, —O—CH═CH— or —(CH₂)_(n+2)—, whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, M means C₁-C₆-alkyl or a group —COR^(b), CO₂R^(b), —O—R^(b), or —NR^(c)R^(d), whereby R^(b) means a hydrogen or a C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkinyl, C₃-C₁₀-cycloalkyl, C₆-C₁₂-aryl or C₁-C₃-perfluoroalkyl and R^(c) and R^(d), independently of one another, mean a hydrogen, C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkinyl, C₃-C₁₀-cycloalkyl, C₆-C₁₂-aryl, C(O)R^(b) or a hydroxy group, whereby if R^(c) is a hydroxy group, R^(d) can be only one hydrogen, a C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkinyl, C₃-C₁₀-cycloalkyl or C₆-C₁₂-aryl and vice versa, and R^(e) means a hydrogen, C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkinyl, C₃-C₁₀-cycloalkyl or C₆-C₁₂-aryl, and p can be a number from 0-6, or R³ is a radical C═C—R^(g)R^(h), whereby R^(g) and R^(h), independently of one another, are a hydrogen or a C₁-C₈-alkyl, C₂-C₈-alkenyl or C₂-C₈-alkinyl that optionally is substituted in one or more places, in the same way or differently, with X, in which X is a cyano, halogen, hydroxy, nitro, —C(O)R^(b), CO₂R^(b), —O—R^(b), —C(O)—NR^(c)R^(d), —NR^(c)R^(d) with the meanings, already further mentioned above, for R^(b), R^(c) and R^(d), and R^(4a) and R^(4b), independently of one another, mean a hydrogen atom, a C₁-C₄-alkyl, a C₂-C₄-alkenyl or together with the ring-carbon atom forming a 3- to 6-membered ring, A means a monocyclic or bicyclic, carbocyclic or heterocyclic aromatic ring, which optionally can be substituted in one or more places with C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkinyl, C₁-C₆-perfluoroalkyl, C₁-C₆-perfluoroalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy, (CH₂)_(p)—C₃-C₁₀-cycloalkyl, (CH₂)_(p)-heterocycloalkyl, (CH₂)_(p)CN, (CH₂)_(p)Hal, (CH₂)_(p)NO₂, (CH₂)_(p)—C₆-C₁₂-aryl, (CH₂)_(p)-heteroaryl, —(CH₂)_(p)PO₃(R^(b))₂, —(CH₂)_(p)NR^(c)R^(d), —(CH₂) NR^(e)COR^(b), —(CH₂)_(p)NR^(e)CSR^(b), —(CH₂)_(p)NR^(e)S(O)R^(b), —(CH₂)_(p)NR^(e)S(O)₂R^(b), —(CH₂)_(p)NR^(e)CONR^(c)R^(d), —(CH₂)_(p)NR^(e)COOR^(b), —(CH₂)_(p)NR^(e)C(NH)NR^(c)R^(d), —(CH₂)_(p)NR^(e)CSNR^(c)R^(d), —(CH₂)_(p)NR^(e)S(O)NR^(c)R^(d), —(CH₂)_(p)NR^(e)S(O)₂NR^(c)R^(d), —(CH₂)_(p)COR^(b), —(CH₂)_(p)CSR^(b), —(CH₂)_(p) S(O)R^(b), —(CH₂)_(p)S(O)(NH)R^(b), —(CH₂)_(p)S(O)₂R^(b), —(CH₂)_(p)S(O)₂NR^(c)R^(d), —(CH₂)_(p)SO₂OR^(b), —(CH₂)_(p)CO₂R^(b), —(CH₂)_(p)CONR^(c)R^(d), —(CH₂)_(p)CSNR^(c)R^(d), —(CH₂)_(p)OR^(b), —(CH₂)_(p)SR^(b), —(CH₂)_(p)CR^(b)(OH)—R^(d), —(CH₂)_(p)—C═NOR^(b), —O—(CH₂), —O—, —O—(CH₂), —CH₂—, —O—CH═CH— or —(CH₂)_(n+2)—, whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or A means a radical —CO₂R^(b), C(O)NR^(c)R^(d), COR^(b), or A means an alkenyl group —CR⁵═CR⁶R⁷, whereby R⁵, R⁶ and R⁷ are the same or different and, independently of one another, mean hydrogen atoms, halogen atoms, aryl radicals or an unsubstituted or partially or completely fluorinated C₁-C₅-alkyl group, or A means an alkinyl group —C≡CR⁵, with the meaning cited above for R⁵, and B means a carbonyl group or a CH₂ group as well as their pharmaceutically acceptable salts.
 2. Compounds according to claim 1, in which R¹ and R² preferably mean a hydrogen atom, a methyl group or an ethyl group.
 3. Compounds according to claim 1, in which R¹ and R² preferably together with the C atom of the chain form a ring with a total of 3 to 7 links.
 4. Compounds according to claim 1, in which R³ preferably means alkenyl, alkinyl, arylalkinyl, heteroarylalkinyl, cycloalkylalkinyl, or heterocycloalkylalkinyl.
 5. Compounds according to claim 1, in which R³ preferably means a vinyl, ethinyl, propinyl, butinyl, pentinyl, hexinyl, heptinyl, octinyl, hydroxypropinyl, hydroxybutinyl, 3-hydroxy-3-methylbutinyl, hydroxypentinyl, carboxypropinyl, t-butylcarboxypropinyl, phenylethinyl, (hydroxyphenyl)ethinyl, (methoxyphenyl)ethinyl, (dimethylaminophenyl)ethinyl, (methylphenyl)ethinyl, (cyanophenyl)ethinyl, (trifluoromethyl)ethinyl, (diphenyl)ethinyl, (nitrophenyl)ethinyl, (tert-butylphenyl)ethinyl, (acetylphenyl)ethinyl, (acetoxyphenyl)ethinyl, (carboxyphenyl)ethinyl or a benzylethinyl group.
 6. Compounds according to claim 1, in which A is preferably an aromatic ring.
 7. Compounds according to claim 1, in which A is preferably a phenyl or naphthyl radical.
 8. Compounds according to claim 7, in which A preferably is an unsubstituted phenyl radical or optionally a phenyl radical that is substituted in one or more places.
 9. Compounds according to claim 8, whereby the phenyl radical is preferably substituted with one or two halogen atoms or a trifluoromethyl group.
 10. Compounds according to claim 9, in which the halogen atoms are preferably chlorine and/or fluorine.
 11. Compounds according to claim 1, in which A preferably is an —O—(CH₂)_(n)—O— or —O—(CH₂)_(n)—CH₂-substituted phenyl ring, whereby the respectively directly adjacent ring-carbon atoms are linked.
 12. Compounds according to claim 1, in which R^(4a) and R^(4b), independently of one another, in each case are a hydrogen atom.
 13. Compounds according to claim 1, namely:

Racemic or No. Enantiomer R3 1 2 3 rac +−

4 5 6 rac +−

7 8 9 rac +−

10 11 12 rac +−

13 14 15 rac +−

16 17 18 rac +−

19 20 21 rac +−

22 23 24 rac +−

25 26 27 rac +−

28 29 30 rac +−

31 32 33 rac +−

34 35 36 rac +−

37 38 39 rac +−

40 41 42 rac +−

43 44 45 rac +−

46 47 48 rac +−

49 50 51 rac +−

52 53 54 rac +−

55 56 57 rac +−

58 59 60 rac +−

Racemic or No. Enantiomer R3 61 62 63 rac +−

64 65 66 rac +−

67 68 69 rac +−

70 71 72 rac +−

73 74 75 rac +−

76 77 78 rac +−

79 80 81 rac +−

82 83 84 rac +−

85 86 87 rac +−

88 89 90 rac +−

91 92 93 rac +−

94 95 96 rac +−

97 98 99 rac +−

100 101 102 rac +−

103 104 105 rac +−

106 107 108 rac +−

109 110 111 rac +−

112 113 114 rac +−

115 116 117 rac +−

118 119 120 rac +−

Racemic or No. Enantiomer R3 121 122 123 rac +−

124 125 126 rac +−

127 128 129 rac +−

130 131 132 rac +−

133 134 135 rac +−

136 137 138 rac +−

139 140 141 rac +−

142 143 144 rac +−

145 146 147 rac +−

148 149 150 rac +−

151 152 153 rac +−

154 155 156 rac +−

157 158 159 rac +−

160 161 162 rac +−

163 164 165 rac +−

166 167 168 rac +−

169 170 171 rac +−

172 173 174 rac +−

175 176 177 rac +−

178 179 180 rac +−

Racemic or No. Enantiomer R3 181 182 183 rac +−

184 185 186 rac +−

187 188 189 rac +−

190 191 192 rac +−

193 194 195 rac +−

196 197 198 rac +−

199 200 201 rac +−

202 203 204 rac +−

205 206 207 rac +−

208 209 210 rac +−

211 212 213 rac +−

214 215 216 rac +−

217 218 219 rac +−

220 221 222 rac +−

223 224 225 rac +−

226 227 228 rac +−

229 230 231 rac +−

232 233 234 rac +−

235 236 237 rac +−

238 239 240 rac +−

Racemic or No. Enantiomer R3 241 242 243 rac +−

244 245 246 rac +−

247 248 249 rac +−

250 251 252 rac +−

253 254 255 rac +−

256 257 258 rac +−

259 260 261 rac +−

262 263 264 rac +−

265 266 267 rac +−

268 269 270 rac +−

271 272 273 rac +−

274 275 276 rac +−

277 278 279 rac +−

280 281 282 rac +−

283 284 285 rac +−

286 287 288 rac +−

289 290 291 rac +−

292 293 294 rac +−

295 296 297 rac +−

298 299 300 rac +−

Racemic or No. Enantiomer R3 301 302 303 rac +−

304 305 306 rac +−

307 308 309 rac +−

310 311 312 rac +−

313 314 315 rac +−

316 317 318 rac +−

319 320 321 rac +−

322 323 324 rac +−

325 326 327 rac +−

328 329 330 rac +−

331 332 333 rac +−

334 335 336 rac +−

337 338 339 rac +−

340 341 342 rac +−

343 344 345 rac +−

346 347 348 rac +−

349 350 351 rac +−

352 353 354 rac +−

355 356 357 rac +−

358 359 360 rac +−

Racemic or No. Enantiomer R3 361 362 363 rac +−

364 365 366 rac +−

367 368 369 rac +−

370 371 372 rac +−

373 374 375 rac +−

376 377 378 rac +−

379 380 381 rac +−

382 383 384 rac +−

385 386 387 rac +−

388 389 390 rac +−

391 392 393 rac +−

394 395 396 rac +−

397 398 399 rac +−

400 401 402 rac +−

403 404 405 rac +−

406 407 408 rac +−

409 410 411 rac +−

412 413 414 rac +−

415 416 417 rac +−

418 419 420 rac +−

Racemic or No. Enantiomer R3 421 422 423 rac +−

424 425 426 rac +−

427 428 429 rac +−

430 431 432 rac +−

433 434 435 rac +−

436 437 438 rac +−

439 440 441 rac +−

442 443 444 rac +−

445 446 447 rac +−

448 449 450 rac +−

451 452 453 rac +−

454 455 456 rac +−

457 458 459 rac +−

460 461 462 rac +−

463 464 465 rac +−

466 467 468 rac +−

469 470 471 rac +−

472 473 474 rac +−

475 476 477 rac +−

478 479 480 rac +−

Racemic or No. Enantiomer R3 481 482 483 rac +−

484 485 486 rac +−

487 488 489 rac +−

490 491 492 rac +−

493 494 495 rac +−

496 497 498 rac +−

499 500 501 rac +−

502 503 504 rac +−

505 506 507 rac +−

508 509 510 rac +−

511 512 513 rac +−

214 515 516 rac +−

517 518 519 rac +−

520 521 522 rac +−

523 524 525 rac +−

526 227 528 rac +−

529 530 531 rac +−

532 533 534 rac +−

535 536 537 rac +−

538 539 540 rac +−

Racemic or No. Enantiomer R3 541 542 543 rac +−

544 545 546 rac +−

547 548 549 rac +−

550 551 552 rac +−

553 554 555 rac +−

556 557 558 rac +−

559 560 561 rac +−

562 563 564 rac +−

565 566 567 rac +−

568 569 570 rac +−

571 572 573 rac +−

574 575 576 rac +−

577 578 579 rac +−

580 581 582 rac +−

583 584 585 rac +−

586 587 588 rac +−

589 590 591 rac +−

592 593 594 rac +−

595 596 597 rac +−

598 599 600 rac +−

Racemic or No. Enantiomer R3 601 602 603 rac +−

604 605 606 rac +−

607 608 609 rac +−

610 611 612 rac +−

613 614 615 rac +−

616 617 618 rac +−

619 620 621 rac +−

622 623 624 rac +−

625 626 627 rac +−

628 629 630 rac +−

631 632 633 rac +−

634 635 636 rac +−

637 638 639 rac +−

640 641 642 rac +−

643 644 645 rac +−

646 647 648 rac +−

649 650 651 rac +−

652 653 654 rac +−

655 656 657 rac +−

658 659 660 rac +−

Racemic or No. Enantiomer R3 661 662 663 rac +−

664 665 666 rac +−

667 668 669 rac +−

670 671 672 rac +−

673 674 675 rac +−

676 677 678 rac +−

679 680 681 rac +−

682 683 684 rac +−

685 686 687 rac +−

688 689 690 rac +−

691 692 693 rac +−

694 695 696 rac +−

697 698 699 rac +−

700 701 702 rac +−

703 704 705 rac +−

706 707 708 rac +−

709 710 711 rac +−

712 713 714 rac +−

715 716 717 rac +−

718 719 720 rac +−

Racemic or No. Enantiomer R3 721 722 723 rac +−

724 725 726 rac +−

727 728 729 rac +−

730 731 732 rac +−

733 734 735 rac +−

736 737 738 rac +−

739 740 741 rac +−

742 743 744 rac +−

745 746 747 rac +−

748 749 750 rac +−

751 752 753 rac +−

754 755 756 rac +−

757 758 759 rac +−

760 761 762 rac +−

763 764 765 rac +−

766 767 768 rac +−

769 770 771 rac +−

772 773 774 rac +−

775 776 777 rac +−

778 779 780 rac +−

Racemic or No. Enantiomer R3 781 782 783 rac +−

784 785 786 rac +−

787 788 789 rac +−

790 791 792 rac +−

793 794 795 rac +−

796 797 798 rac +−

799 800 801 rac +−

802 803 804 rac +−

805 806 807 rac +−

808 809 810 rac +−

811 812 813 rac +−

814 815 816 rac +−

817 818 819 rac +−

820 821 822 rac +−

823 824 825 rac +−

826 827 828 rac +−

829 830 831 rac +−

832 833 834 rac +−

835 836 837 rac +−

838 839 840 rac +−

Racemic or No. Enantiomer R3 841 842 843 rac +−

844 845 846 rac +−

847 848 849 rac +−

850 851 852 rac +−

853 854 855 rac +−

856 857 858 rac +−

859 860 861 rac +−

862 863 864 rac +−

865 866 867 rac +−

868 869 870 rac +−

871 872 873 rac +−

874 875 876 rac +−

877 878 879 rac +−

880 881 882 rac +−

883 884 885 rac +−

886 887 888 rac +−

889 890 891 rac +−

892 893 894 rac +−

895 896 897 rac +−

898 899 900 rac +−

Racemic or No. Enantiomer R3 901 902 903 rac +−

904 905 906 rac +−

907 908 909 rac +−

910 911 912 rac +−

913 914 915 rac +−

916 917 918 rac +−

919 920 921 rac +−

922 923 924 rac +−

925 926 927 rac +−

928 929 930 rac +−

931 932 933 rac +−

934 935 936 rac +−

937 938 939 rac +−

940 941 942 rac +−

943 944 945 rac +−

946 947 948 rac +−

949 950 951 rac +−

952 953 954 rac +−

955 956 957 rac +−

958 959 960 rac +−

Racemic or No. Enantiomer R3  961  962  963 rac +−

 964  965  966 rac +−

 967  968  969 rac +−

 970  971  972 rac +−

 973  974  975 rac +−

 976  977  978 rac +−

 979  980  981 rac +−

 982  983  984 rac +−

 985  986  987 rac +−

 988  989  990 rac +−

 991  992  993 rac +−

 994  995  996 rac +−

 997  998  999 rac +−

1000 1001 1002 rac +−

1003 1004 1005 rac +−

1006 1007 1008 rac +−

1009 1010 1011 rac +−

1012 1013 1014 rac +−

1015 1016 1017 rac +−

1018 1019 1020 rac +−

Racemic or No. Enantiomer R3 1021 1022 1023 rac +−

1024 1025 1026 rac +−

1027 1028 1029 rac +−

1030 1031 1032 rac +−

1033 1034 1035 rac +−

1036 1037 1038 rac +−

1039 1040 1041 rac +−

1042 1043 1044 rac +−

1045 1046 1047 rac +−

1048 1049 1050 rac +−

1051 1052 1053 rac +−

1054 1055 1056 rac +−

1057 1058 1059 rac +−

1060 1061 1062 rac +−

1063 1064 1065 rac +−

1066 1067 1068 rac +−

1069 1070 1071 rac +−

1072 1073 1074 rac +−

1075 1076 1077 rac +−

1078 1079 1080 rac +−

Racemic or No. Enantiomer R3 1081 1082 1083 rac +−

1084 1085 1086 rac +−

1087 1088 1089 rac +−

1090 1091 1092 rac +−

1093 1094 1095 rac +−

1096 1097 1098 rac +−

1099 1100 1101 rac +−

1102 1103 1104 rac +−

1105 1106 1107 rac +−

1108 1109 1110 rac +−

1111 1112 1113 rac +−

1114 1115 1116 rac +−

1117 1118 1119 rac +−

1120 1121 1122 rac +−

1123 1124 1125 rac +−

1126 1127 1128 rac +−

1129 1130 1131 rac +−

1132 1133 1134 rac +−

1135 1136 1137 rac +−

1138 1139 1140 rac +−

Racemic or No. Enantiomer R3 1141 1142 1143 rac +−

1144 1145 1146 rac +−

1147 1148 1149 rac +−

1150 1151 1152 rac +−

1153 1154 1155 rac +−

1156 1157 1158 rac +−

1159 1160 1161 rac +−

1162 1163 1164 rac +−

1165 1166 1167 rac +−

1168 1169 1170 rac +−

1171 1172 1173 rac +−

1174 1175 1176 rac +−

1177 1178 1179 rac +−

1180 1181 1182 rac +−

1183 1184 1185 rac +−

1186 1187 1188 rac +−

1189 1190 1191 rac +−

1192 1193 1194 rac +−

1195 1196 1197 rac +−

1198 1199 1200 rac +−

Racemic or No. Enantiomer R3 1201 1202 1203 rac +−

1204 1205 1206 rac +−

1207 1208 1209 rac +−

1210 1211 1212 rac +−

1213 1214 1215 rac +−

1216 1217 1218 rac +−

1219 1220 1221 rac +−

1222 1223 1224 rac +−

1225 1226 1227 rac +−

1228 1229 1230 rac +−

1231 1232 1233 rac +−

1234 1235 1236 rac +−

1237 1238 1239 rac +−

1240 1241 1242 rac +−

1243 1244 1245 rac +−

1246 1247 1248 rac +−

1249 1250 1251 rac +−

1252 1253 1254 rac +−

1255 1256 1257 rac +−

1258 1259 1260 rac +−

Racemic or No. Enantiomer R3 1261 1262 1263 rac +−

1264 1265 1266 rac +−

1267 1268 1269 rac +−

1270 1271 1272 rac +−

1273 1274 1275 rac +−

1276 1277 1278 rac +−

1279 1280 1281 rac +−

1282 1283 1284 rac +−

1285 1286 1287 rac +−

1288 1289 1290 rac +−

1291 1292 1293 rac +−

1294 1295 1296 rac +−

1297 1298 1299 rac +−

1300 1301 1302 rac +−

1303 1304 1305 rac +−

1306 1307 1308 rac +−

1309 1310 1311 rac +−

1312 1313 1314 rac +−

1315 1316 1317 rac +−

1318 1319 1320 rac +−

Racemic or No. Enantiomer R3 1321 1322 1323 rac +−

1324 1325 1326 rac +−

1327 1328 1329 rac +−

1330 1331 1332 rac +−

1333 1334 1335 rac +−

1336 1337 1338 rac +−

1339 1340 1341 rac +−

1342 1343 1344 rac +−

1345 1346 1347 rac +−

1348 1349 1350 rac +−

1351 1352 1353 rac +−

1354 1355 1356 rac +−

1357 1358 1359 rac +−

1360 1361 1362 rac +−

1363 1364 1365 rac +−

1366 1367 1368 rac +−

1369 1370 1371 rac +−

1372 1373 1374 rac +−

1375 1376 1377 rac +−

1378 1379 1380 rac +−

Racemic or No. Enantiomer R3 1381 1382 1383 rac +−

1384 1385 1386 rac +−

1387 1388 1389 rac +−

1390 1391 1392 rac +−

1393 1394 1395 rac +−

1396 1397 1398 rac +−

1399 1400 1401 rac +−

1402 1403 1404 rac +−

1405 1406 1407 rac +−

1408 1409 1410 rac +−

1411 1412 1413 rac +−

1414 1415 1416 rac +−

1417 1418 1419 rac +−

1420 1421 1422 rac +−

1423 1424 1425 rac +−

1426 1427 1428 rac +−

1429 1430 1431 rac +−

1432 1433 1434 rac +−

1435 1436 1437 rac +−

1438 1439 1440 rac +−

Racemic or No. Enantiomer R3 1441 1442 1443 rac +−

1444 1445 1446 rac +−

1447 1448 1449 rac +−

1450 1451 1452 rac +−

1453 1454 1455 rac +−

1456 1457 1458 rac +−

1459 1460 1461 rac +−

1462 1463 1464 rac +−

1465 1466 1467 rac +−

1468 1469 1470 rac +−

1471 1472 1473 rac +−

1474 1475 1476 rac +−

1477 1478 1479 rac +−

1480 1481 1482 rac +−

1483 1484 1485 rac +−

1486 1487 1488 rac +−

1489 1490 1491 rac +−

1492 1493 1494 rac +−

1495 1496 1497 rac +−

1498 1499 1500 rac +−

Racemic or No. Enantiomer R3 1501 1502 1503 rac +−

1504 1505 1506 rac +−

1507 1508 1509 rac +−

1510 1511 1512 rac +−

1513 1514 1515 rac +−

1516 1517 1518 rac +−

1519 1520 1521 rac +−

1522 1523 1524 rac +−

1525 1526 1527 rac +−

1528 1529 1530 rac +−

1531 1532 1533 rac +−

1534 1535 1536 rac +−

1537 1538 1539 rac +−

1540 1541 1542 rac +−

1543 1544 1545 rac +−

1546 1547 1548 rac +−

1549 1550 1551 rac +−

1552 1553 1554 rac +−

1555 1556 1557 rac +−

1558 1559 1560 rac +−

Racemic or No. Enantiomer R3 1561 1562 1563 rac +−

1564 1565 1566 rac +−

1567 1568 1569 rac +−

1570 1571 1572 rac +−

1573 1574 1575 rac +−

1576 1577 1578 rac +−

1579 1580 1581 rac +−

1582 1583 1584 rac +−

1585 1586 1587 rac +−

1588 1589 1590 rac +−

1591 1592 1593 rac +−

1594 1595 1596 rac +−

1597 1598 1599 rac +−

1600 1601 1602 rac +−

1603 1604 1605 rac +−

1606 1607 1608 rac +−

1609 1610 1611 rac +−

1612 1613 1614 rac +−

1615 1616 1617 rac +−

1618 1619 1620 rac +−


14. Pharmaceutical composition that contains at least one compound of general formula I according to claim 1 and optionally at least one additional active ingredient together with pharmaceutically compatible adjuvants and/or vehicles.
 15. Pharmaceutical composition according to claim 14, wherein the additional active ingredient is a SERM (selective estrogen receptor modulator), an aromatase inhibitor, an antiestrogen, or a prostaglandin.
 16. Pharmaceutical composition according to claim 14, whereby the active ingredients can be tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulfinyl]-pentyloxy}phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol, ICI 182 780 (7alpha-[9-(4,4,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17-beta-diol), 11beta-fluoro-7alpha-[5-(methyl {3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17beta-diol, 11beta-fluoro-7alpha-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)-amino]pentyl}estra-1,3,5(10)-triene-3,17beta-diol, 11beta-fluoro-17alpha-methyl-7alpha-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}estra-1,3,5(10)-triene-3,17beta-diol, clomifene, raloxifene, fadrozole, formestane, letrozole, anastrozole or atamestane.
 17. Use of compounds according to claim 1 for the production of a pharmaceutical agent.
 18. Use of compounds according to claim 17 for the production of a pharmaceutical agent for therapy and prophylaxis of gynecological diseases such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhea.
 19. Use of compounds according to claim 17 for the production of a pharmaceutical agent for therapy and prophylaxis of hormone-dependent tumors.
 20. Use of compounds according to claim 17 for the production of a pharmaceutical agent for therapy and prophylaxis of breast cancer.
 21. Use of compounds according to claim 17 for the production of a pharmaceutical agent for therapy and prophylaxis of endometrial carcinoma.
 22. Use of compounds according to claim 17 for the production of a pharmaceutical agent for therapy and prophylaxis of ovarian cancer.
 23. Use of compounds according to claim 17 for the production of a pharmaceutical agent for therapy and prophylaxis of prostate cancer.
 24. Use of compounds according to claim 17 for the production of a pharmaceutical agent for female hormone replacement therapy.
 25. Use of compounds according to claim 17 for female birth control.
 26. Process for the selective addition of lithium alkinyl compounds and magnesium haloalkinyl compounds to ketoamide. 